Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems

Abstract Background Depression is the most disabling neuropsychiatric disorder, causing difficulties in daily life activities and social interactions. The exact mechanisms of depression remain largely unclear. However, some studies have shown that mitochondrial dysfunction would play a crucial role in the occurrence and development of depression. Aims To summarize the known knowledge about the role of mitochondrial dysfunction in the pathogenesis of depression. Methods We review the recent literature， including 105 articles, to summarize the mitochondrial energy metabolism and quality control systems in the occurrence and development of depression. Some antidepressants which may exert their effects by improving mitochondrial function are also discussed. Results Impaired brain energy metabolism and (or) damaged mitochondrial quality control systems have been reported not only in depression patients but in animal models of depression. Although the classical antidepressants have not been specially designed to target mitochondria, the evidence suggests that many antidepressants may exert their effects by improving mitochondrial function. Conclusions This brief review focuses on the findings that implicate mitochondrial dysfunction and the quality control systems as important etiological factors in the context of depressive disorders. It will help us to understand the various concepts of mitochondrial dysfunction in the pathogenesis of depression, and to explore novel and more targeted therapeutic approaches for depression.

further exploration is needed to uncover the pathophysiological mechanisms underlying depression.
Mitochondria are ubiquitous double membrane-bound organelles found in almost all eukaryotic cells.They are most prominently known for playing a pivotal role in energy production and being involved in complex physiological activities such as energy metabolism, cell survival, and nervous system development. 6Moreover, mitochondrial dysfunction not only impairs energy production but can also be linked with metabolic and neuropsychiatric disorders such as depression. 4[9] The review will focus on the findings that implicate abnormalities in mitochondrial morphology and function, as well as the resultant quality control systems as important etiological factors in the context of depressive disorders.

| MITOCHONDRIAL MORPHOLOGY AND DEPRE SS ION
1][12] Previous studies from bipolar disorder patients have shown that neurons in the postmortem prefrontal cortices have significantly a larger number of small mitochondria, whereas mitochondria in peripheral cells display an abnormal pattern of clumping and marginalization in the intracellular distribution, suggesting subtle changes in the critical network architecture of mitochondria in the neurons. 10,13The similar results have been revealed in the animal models.Gebara et al. 12 demonstrated that high-anxious rats exhibit more severe depression-like behavior, and present larger mitochondria area and mitochondria tissue coverage as well as a higher number of mitochondriamitochondria contacts in the medium spiny neurons from the nucleus accumbens (NAc).5][16] Some studies revealed that CUMS can result in abnormal mitochondrial morphology, such as the mitochondrial rupture and impairment in hippocampal astrocytes, and the significant mitochondrial swelling, broken mitochondrial cristae, and decreased mitochondrial matrix density in hippocampus. 17,18Additionally, our previous study demonstrated that the prenatal dexamethasone (Dex) exposure leads to depression-like behavior and mitochondrial damage in hippocampus, including a decrease in cristae density or even the disappearance, vacuole formation by the mitochondrial outer membrane extension, as well as the intermembrane space expansion, which can be improved by exercise. 11Taken together, these studies corroborate the close coupling between the abnormal mitochondrial morphology and the development of depression.

| MITOCHONDRIAL ENERGY ME TABOLIS M AND DEPRE SS ION
As mentioned, mitochondria are bioenergetic organelles that meet most of the energy needs of organisms by providing adenosine triphosphate (ATP).The metabolism of glucose, lipids, and proteins is connected through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation, which also requires mitochondria. 19Of note, mitochondria are particularly important for brain because of both its high levels of energy use and inability to store large amounts of energy reserves in the form of glycogen.As glucose metabolism supplies more than 95% of ATP in the brain, this may strongly suggests the intriguing possibility that decreased ATP level caused by mitochondrial disorders is critically involved in neurological diseases, including depression. 20,21 the past decade, evidence from some patients with major depressive disorder (MDD) exhibits decreased glucose metabolism level in some brain regions related to emotion regulation, such as bilateral insula, left lentiform nucleus putamen and extra-nuclear, right caudate and cingulate gyrus. 22Similarly, several studies have shown that the beta-nucleoside triphosphate, which arises from beta-ATP, is much lower in the basal ganglia of MDD patients. 23,24Notably, it has also been found that patients with diabetes have a higher risk of depression, and the co-occurrence of diabetes mellitus and depression may be associated with abnormal glucose metabolism and the subsequent decreased ATP in the brain. 25,268][29] For instance, it was reported that CUMS not only induces depression but reduces the ATP content of the prefrontal cortex and hippocampus in mice. 30,31Cao et al. 32 found that chronic social defeat stress reduces ATP abundance in some brain regions, while the lateral intracerebroventricular injection of ATP, or an increase in endogenous ATP released by astrocytes, can significantly improve the depression-like behavior in the mice.Moreover, the study by Alhassen et al. 33 demonstrated that acetyl-L-carnitine supplementation can improve mitochondrial function and promote ATP production, thereby ameliorating depression caused by intergenerational trauma.In addition, it has been shown that prenatal Dex exposure results in depression-like behavior, accompanied by mitochondrial dysfunction and the diminished production of ATP in the frontal cortices or hippocampus of the adult rodents, and that improvement of mitochondrial function in brain improves the depression-like behavior. 11,21,34me studies from human and animals suggest that the deficiency of ATP resulting from mitochondrial disorders contributes to the pathogenesis of depression.It is widely known that ATP is mainly produced by aerobic and anaerobic glycolysis.The former is a series of reactions wherein glucose is converted to pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation, while the later includes glycolysis and lactic acid production, which mainly takes place in the cytoplasm. 6Due to the high energy demands of the brain, the processes of aerobic and anaerobic glycolysis are critical for the proper functioning of the brain, including emotion.Then the roles of aerobic and anaerobic glycolysis in the development of depression are discussed in the following section (Figure 1).

| Aerobic glycolysis
Mitochondrial oxidative phosphorylation is one of the important processes in aerobic glycolysis and requires the mitochondrial respiratory chain, which is composed of various respiratory enzyme complexes and located in a special structure of the inner mitochondrial membrane. 357][38] For instance, postmortem studies showed that the levels of mitochondrial respiratory chain complex I subunits NDUFV1, NDUFV2, and NADUFS1 are reduced in the lateral cerebellar hemisphere of patients with MDD. 39,40Moreover, both mitochondrial respiratory chain complex I and III are also observed to be significantly decreased in the neuron-derived extracellular vesicles (NDEVs) of MDD patients. 41milarly, some animal studies verified that the activity of mitochondrial respiratory chain complex II and V, and the levels of some mitochondrial-respiration proteins, such as cytochrome b-c1 complex subunit 1, ATP synthase subunit O and ATP synthase γ chain, are significantly inhibited in the prefrontal cortex of depressive rodents. 30,42Of note, Damri et al. 38 reported that intraperitoneal administration of rotenone, an inhibitor of mitochondrial respiratory chain complexes, causes depression-like behaviors in mice, which is accompanied by abnormal changes in mitochondrial-respiration proteins levels in hippocampus.
Recently, it has been shown that TCA cycle in aerobic glycolysis is also involved in the development of depression.Linghu et al. 43 revealed depressive rats caused by CUMS show significantly decreased TCA cycle and increased gluconeogenesis pathway, which may be related to the decrease of mitochondrial pyruvate carrier.
It has also been shown that the level of pyruvate dehydrogenase, which is a key enzyme linking glycolysis with the TCA cycle, is significantly decreased in the frontal cortex of prenatal Dex-induced depressive rats.Furthermore, it has been revealed the downregulation of Aco2 in chronic social isolation-sensitive rats, which would imply that the TCA cycle is abnormal. 44Although these findings provide evidence that inhibition of TCA cycle is present in some animal models of depression, it is very hard to explain their connections at current stage.

| Anaerobic glycolysis
Anaerobic glycolysis often occurs in occasions when the regeneration of ATP in mitochondria is insufficient to meet the requirement, such as ischemia, hypoxia, or mitochondrial dysfunction. 45Indeed, in mitochondrial dysfunction conditions, the process of glucose catabolism is impaired, which affects the Krebs cycle and leads to the F I G U R E 1 Schematic diagram of mitochondrial energy metabolism and depression.The blue arrows represent the processes of aerobic and anaerobic glycolysis, and the purple arrows represent electron transport in the electron transport chain (ETC) reaction.The ETC is localized within the inner mitochondrial membrane or cristae of the mitochondria and is composed of five multimeric protein complexes (mitochondrial respiratory chain complex I-IV and ATP synthase) responsible for ATP production by oxidative phosphorylation.The red dashed boxes represent the dysfunction of energy metabolism, which is proved to lead to depression.ADP, adenosine diphosphate; ATP, adenosine triphosphate; CoQ, coenzyme Q; Cyt c, cytochrome c; e-, electron; FAD, flavin adenine dinucleotide; I-IV, mitochondrial respiratory chain complex I-IV; NAD, nicotinamide adenine dinucleotide; TCA, tricarboxylic acid cycle.increase of anaerobic glycolysis, eventually resulting in lactate accumulation. 46Therefore, lactate accumulation is a key indicator of increasing anaerobic glycolysis.
8][49] For example, some MDD patients exhibit higher concentration of lactate in the pregenual anterior ingulated cortex, which is proved to be positively correlated with depression severity. 47,49Moreover, some patients with MDD or bipolar disorder also have increased lactate concentration in ventricular cerebrospinal fluid (CSF). 48Notably, the measurement of lactate concentration in CSF has been considered to be helpful to identify some types of depression.It has been believed that the accumulation of lactate is associated with increased fraction of energy utilization via glycolysis and reduced mitochondrial oxidative clearance of lactate in MDD patients. 47Consistent with human studies, depression model rodents also showed the similar results.
For instance, study from Liu et al. 50demonstrated that CUMS increases lactate concentration in hippocampus in rats.Detka et al. 51 reported that the lactate concentration in the frontal cortex is significantly higher in animals subjected to prenatal stress, which indicates that prenatal stress enhances the synthesis of lactate and glycolysis in response to adverse stimuli acting later in life.The enhanced glycolysis may be a mechanism to compensate for the weakness of the Krebs cycle or oxidative phosphorylation.
The data supports the conclusions that lactate accumulation is in conjunction with depression, which suggests the abnormalities of anaerobic glycolysis are involved in depression.Nevertheless, it remains to be investigated in future studies.

| MITOCHONDRIAL QUALIT Y CONTROL SYS TEMS AND DEPRE SS ION
Mitochondria are not static entities; they need quality control systems to maintain their structural and functional integrity.

| Mitochondrial biogenesis
Mitochondrial biogenesis is a process generating new mitochondrial offspring to maintain an adequate mitochondrial number, therefore to compensate the ATP deficiency or energy crises. 72Disrupted mitochondrial biogenesis diminishes the mitochondrial mass, accelerates mitochondrial senescence, and then promotes mitochondrial dysfunction.An increasing body of evidence indicates that the main factors affecting mitochondrial biogenesis include transcriptional coactivator peroxisome proliferator-activated receptorγ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF1), nuclear respiratory factor 2 (NRF2), 5′-AMP activated protein kinase (AMPK), Sirtuin1 (SIRT1), mitochondrial transcription factor A (TFAM), etc. 56,57 The alterations of these above-mentioned factors may interrupt mitochondrial biogenesis, and then induce mitochondrial dysfunction, eventually leading to depression. 41,53,57,58,73 is known that PGC-1α, termed the "master regulator of mitochondrial biogenesis," plays an important role in the etiology of depressive disorders.For instance, it was reported that some patients with psychotic unipolar depression exhibit lower PGC-1α level in whole-blood. 56Similarly, the expression of PGC-1α and its downstream genes TFAM and NRF1, is observed to be downregulated in blood monocyte cells in patients with MDD. 57Interestingly, an animal study performed by Yan et al. 55 demonstrated that PGC-1α has been implicated in stress and resilience to stress-induced depressionlike behaviors.Yang et al. 59 reported that a high-fat diet can induce depression-like behavior in mice through leading to inhibition of the CREB/PGC-1α signal pathway and mitochondrial dysfunction in hippocampus.Additionally, the study from Hu et al. 58 has shown that CUMS rats show the disrupted mitochondrial biogenesis in hippocampus, which is closely linked to the reduction of PGC-1α, ERRα, and FNDC5, and the BDNF expression and inhibition of PGC-1α/FNDC5/ BDNF pathway.Similarly, Wu et al. 53 have reported that the expression of PGC-1α is decreased in the hippocampus of CUMS rats, and curcumin, a traditional Chinese medicine ingredient, is able to alleviate the depression-like behavior by enhancing the expression of PGC-1α and promoting mitochondrial biogenesis.The study by Hu et al. 74 also demonstrated that the novel antidepressant Esketamine could provide an noticeable antidepressant effect through activating PGC-1α/ irisin/ERK1/2 signaling pathway in the hippocampus of CUMS mice.
Taken together, PGC-1α and its signaling pathway play an important role in depression, which may be related to mitochondrial biogenesis.
Consistent with PGC-1α, other genes, such as NRF2, AMPK and SIRT1 are also associated with mitochondrial biogenesis and depression. 41,61It is reported that NRF2 might promote the expression of TFAM and drive transcription and replication of mtDNA, and some patients with MDD frequently show lower NRF2 level in NDEVs. 41reover, it has been shown that the pAMPK level, which acts as an energy sensor of the cell and a key regulator of mitochondrial biogenesis, is significantly inhibited in hippocampus and prefrontal cortex of depressive rats caused by Dex exposure. 60In addition, Lei et al. 61 found that the ablation of SIRT1 in cortical and hippocampal glutamatergic neurons can reduce mitochondrial density and mitochondrial biogenesis, resulting in depression-like behavior in male mice, while SIRT1 activator promotes mitochondrial biogenesis and exhibits an antidepressant-like effect.Conversely, Kim et al. 75 found that chronic social defeat stress increases SIRT1 levels in the NAc, which mediates depression-and anxiety-like behaviors.These conflicting results may be due to differences in specific brain regions, cell type-specific roles, signaling pathways downstream, and rodent model used.Further work is needed to address this complexity.

| Mitophagy
Mitophagy is a vital pathway that selectively removes defective mitochondria through the process of autophagy, which can affect mitochondrial quality and quantity, thereby maintaining mitochondrial and cellular homeostasis. 76Indeed, an impairment of the mitophagy pathway may trigger the gradual accumulation of defective mitochondria, then lead to mitochondrial dysfunction, and further participate in the development of neuropsychiatric diseases such as depression. 77Data from some MDD participants shows that the clearance of damaged mitochondria is impaired in peripheral blood mononuclear cells (PBMCs) through assessing some markers of mitochondria. 54In animal models of depression, it is reported that although many autophagosomes are found in the hippocampal neurons of CUMS mice, but neither mitophagosomes nor mitolysosomes are seen, which indicates that the mitophagy is inhibited by CUMS. 66milarly, Wang et al. 78   ubiquitin (Ub)-dependent pathway. 79Some studies have reported that low PINK1/Parkin levels and the subsequent mitophagy inhibition may be important pathogenic factors for depression. 17,63cent studies have shown that some MDD patients have lower level of Parkin in the PBMCs. 54,64Interestingly, from the perspective of gene mutation, higher depression index has been reported in Parkinson's disease patients with homozygous or compound heterozygous Parkin mutations, suggesting there may be a close relationship between this mitophagy pathway and depression. 62 animal models, it is demonstrated that PINK1 deficiency decreases the threshold for chronic stress-induced depression, indicating that defective mitophagy is linked to the pathogenesis of depression. 63TOMM20 is found to be a mitochondrial outermembrane protein which can be degraded by E3 ubiquitin ligase Parkin recruited by PINK1.Shu et al. 17 reported that glucocorticoid inhibits the mitochondrial translocation of Parkin and TOMM20 degradation in primary hippocampal astrocytes of chronic mild stress mice model, which disrupts the process of mitophagy and contributes to depression.
More recently, several mitophagy receptors (Ub-independent pathway) can directly induce mitophagy, which include outer mitochondrial membrane (OMM) proteins such as BCL2 interacting protein 3 like (BNIP3L/NIX or NIX), BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3). 80A growing body of studies has shown that these OMM proteins participate in the process of autophagy and mitophagy, and have a wide range of physiological and behavioral effects. 65,81However, few researches focus on the effects of OMM proteins on depression.For example, Choi et al. 65 revealed that glucocorticoids exposure, which is the well-known risk factor of depression, damages NIX-dependent mitophagy and subsequent synaptic homeostasis, while the restoration of NIX level reverses this effect.More recently, Jin et al. 66 reported that CUMS inhibits the NIX expression and mitophagy in hippocampus, eventually leading to the depression-like behavior in mice.And they also found that the enhancement of NIX-mediated mitophagy ameliorates the depression induced by CUMS.

| Mitochondrial fusion and fission
Mitochondrial fusion is a process that allows content mixing between intact and dysfunctional mitochondria, whereas fission is the process that includes sequestration of irreversibly damaged, fusionincompetent mitochondria and their subsequent elimination by autophagy. 82As replacement of damaged mitochondria contributes to the integrity and homogeneity of the mitochondrial population in a cell, both mitochondrial fusion and fission are coordinated to maintain homeostasis of the mitochondria in the cellular stress response.
Therefore, erroneous mitochondrial fission or fusion promotes the formation of mitochondrial fragments that contain damaged mitochondrial DNA, and exhibits impaired oxidative phosphorylation. 83 has been illustrated that the levels of mitofusin (Mfn) 1 and 2, and Optic Atrophy 1 (Opa1) are involved in mitochondrial fusion, whereas the level of dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1) are involved in mitochondrial fission.The aberrant expression of these genes reflects impaired mitochondrial fusion and fission. 84tochondrial fusion mainly depends on distinct mitochondrial sublocalization of three fusogenic proteins: the OMM-located Mfn1 and Mfn2, and the inner mitochondrial membranes (IMM)-located Opa1.Mfn1 and Mfn2 are transmembrane GTPases located on the mitochondrial outer membrane, acting as key mediators of mitochondrial fusion. 85Clinical research has shown that Mfn2 level is reduced strikingly in the NDEVs of MDD patients, but it can be reversed through treatment of a selective serotonin reuptake inhibitor (SSRI). 41However, Scaini et al. 54 reported that some MDD patients have increased levels of Mfn2 and Opa1 in the PBMCs.It suggests that mitochondrial fusion-related proteins expression is complicated in depressive patients.Interestingly, in rodents, it was reported that Mfn2 expression is downregulated in the NAc of outbred rats, which show depression-like and anxiety-like behaviors. 12According to the studies of Liu et al., 68 CUMS or glucocorticoids treatment decreases the expression of Mfn1 and Mfn2 in the cerebral cortex of rats, which regulates depression-like behavior.Additionally, it is also demonstrated that the expression of mitochondrial fusion genes Mfn1, Mfn2, and Opa1 is decreased in hippocampus and frontal cortex of depressive mice comorbid with diabetes. 69Nevertheless, Feng et al. 67 found that the expression of Mfn1 and Mfn2 is increased in the hippocampus of depressive rats caused by prenatal restraint stress, indicating prenatal stress promotes mitochondrial fusion.The differences in experimental subjects and conditions may be responsible for this discrepancy, in particular, the heterogeneous expression of mitochondrial fusion proteins in different types of depression or animal models of depression. 54ior studies have demonstrated that some factors, such as Drp1and Fis1, are the key mediators to trigger mitochondrial fission.Drp1, a GTPase, can be recruited to the mitochondrial outer membrane to regulate mitochondrial fission in cellular stress response. 86Fis1, a mitochondrial outer membrane protein, participates in the recruitment of Drp1 through its cytosolic domain, and plays a similar role in mitochondrial fission as Drp1.There is few studies on the relationship between mitochondrial fission and depression.Recently, Tabassum et al. 70 have demonstrated Drp1 level is significantly increased in hippocampus of depressive mice induced by CUMS.Moreover, Deng et al. 71 have also shown that both Drp1 and Fis1 levels are increased in the hippocampus of depressive rats induced by maternal separation, while the antidepressant administration can reverse the abnormal expression of Drp1 and Fis1.

| ANTIDEPRE SSANTS AND MITOCHONDRIA
Most classical antidepressants, such as tricyclic antidepressants (TCAs), SSRIs, and serotonin-noradrenaline reuptake inhibitors (SNRIs), mainly target monoamine neurotransmitter system. 87vertheless, 30% of the patients do not achieve remission with the available antidepressant drugs, and a big percentage of treated patients present adverse reactions.Now, some novel drugs, such as Baicalin, Memantine, XiaoYaoSan, Oridonin, Brexanolone, Zuranolone, Ketamine, etc., have also been used clinically on patients with depression. 88,89nsidering the important roles of mitochondrial disturbances in the development of depression, many researchers have been studying on the relationship between antidepressant mechanisms of the drugs and mitochondria.It has been demonstrated that some recent FDA-approved antidepressants, such as Brexanolone and Zuranolone, can stimulate the production of endogenous neurosteroids through the translocator protein 18 kDa (TSPO), which is a transmembrane protein located primarily in mitochondria.
And the neurosteroidogenic capacity of mitochondria and their regulation by TSPO may promise avenue for innovative therapeutic approaches within the complex interplay of factors contributing to depression. 90Moreover, Chen et al. 91 demonstrated that Vortioxetine can rapidly form functional synapses in hippocampus of rats with mitochondrial support, which may be one of the reasons for its antidepressant effect.Additionally, it has been reported that Agomelatine can stabilize mitochondrial membrane stability through the Bax/Bcl2 balance and alleviate hippocampus damage in aging rats induced by D-galactose. 92However, in fact, more studies on the effects of antidepressants on mitochondria are still focus on energy metabolism and quality control systems.

| Antidepressants improve the mitochondrial energy metabolism
As the abnormality of mitochondrial oxidative phosphorylation is closely associated with the pathogenesis of depression, 21 multiple pieces of evidence suggest that antidepressants may ameliorate depression-like behavior by enhancing the activity of the mitochondrial respiratory chain and the ATP production.For instance, it was observed that chronic Tianeptine administration up-regulates the expression of mitochondrial energy metabolism-related enzymes, such as Atp5b, Atp5o and Cytc, in hippocampal synaptosomal fractions of rats exposed to chronic social isolation. 93Moreover, Scaini et al. 37 noted that the chronic administration of paroxetine increases the activities of mitochondrial respiratory chain complex I and complex II in the hippocampus, striatum, and cerebral cortex.They also reported that the administration of venlafaxine enhances mitochondrial respiratory chain complex II activity in the same brain regions, as well as increases complex IV activity only in the prefrontal cortex.Furthermore, it has been shown that novel drugs Baicalin and Memantine increase the activities of the mitochondrial respiratory chain complex I and complex V, as well as improve the mitochondrial function, and then enhance the ATP level in the brain of CUMS depressive mice. 30,88These results support the conclusions that some antidepressants may exert their antidepressant effects at least partly by enhancing the expression of respiratory chain complexes and improving mitochondrial energy metabolism in brain.Inconsistent with the results, other studies reported that some antidepressants have different effects on mitochondria.Ľupták M et al. 94 conducted a study demonstrating that the novel antipsychotics and antidepressants, including Brexpiprazole, Cariprazine, Loxapine, and Lurasidone, primarily inhibit individual ETC complexes and significantly decreased mitochondrial ATP production at higher concentrations.The paradox should be interpreted with caution due to the overdose of the drugs, which may lead to side effects of them.Notably, different correlation coefficients were observed for individual drugs concerning changes in the activity of specific ETC complexes and mitochondrial function, suggesting some specificity of the mitochondrial effects of individual psychopharmaca. 94,95In addition, some studies in vivo have also shown that antidepressants often lead to upregulation of mitochondrial activity in various metabolic pathways during acute treatment, while chronic treatment leads to reduced or no change in mitochondrial activity. 94,96Therefore, further work is needed to address this complexity.
It has been shown that some antidepressants can also affect other stages of aerobic glycolysis.For example, it has been demonstrated that chronic fluoxetine treatment enhances the expression of components of the pyruvate dehydrogenase complex in the frontal cortex of prenatal stress-induced depressive rats. 97Wu et al. 98 have also demonstrated that the antidepressant XiaoYaoSan increases the enzyme activity of lactate dehydrogenase in the hippocampus of CUMS rats, indicating that the antidepressant can modulate the disorders of glucose catabolism in chronic stress-caused depressive rats.Of note, these preclinical studies linking mitochondrial energy metabolism and antidepression may provide a new insight to explore the new antidepressants and their underlying mechanisms.

| Antidepressants amend the mitochondrial quality control systems
As impaired mitochondrial quality control systems are closely associated with depression, 66 some studies revealed that some antidepressants can improve the abnormality of mitochondrial quality control systems in some kinds of animal models of depression.For instance, it has been demonstrated that chronic fluoxetine treatment upregulates the protein expression of the mitochondrial DJ-1, which engaged in mitochondrial biogenesis, in the hippocampus of prenatally stressed offspring rats. 99Resveratrol, a naturally occurring polyphenolic antioxidant, is able to increase the mRNA expression of SIRT1 and PGC-1α, and then promote mitochondrial biogenesis, eventually enhancing ATP level in the hippocampus of mice exposed to CUMS. 31 A study by Lin et al. 100 verified that Metformin significantly increases the mRNA levels of NRF1 and TFAM in the hippocampus of aged apoE4-TR mice, performing the metforminmediated antidepressant-like effect.These findings suggest it exists universally that antidepressant effects are consistent with improving mitochondrial biogenesis.
In mitophagy, previous studies have shown that fluoxetine increases the expression of NIX and enhances NIX-mediated mitophagy in the hippocampus of CUMS mice. 65,66Notably, Ketamine, a rapid on-set and long-lasting antidepressant, particularly in patients with treatment-resistant depression, reverses the TNFα-induced behavior despair through activation of NIX-mediated mitophagy in the medial prefrontal cortex. 101Interestingly, Oridonin, the major active ingredient of the traditional Chinese medicinal herb Rabdosia rubescens, enhances mitophagy in LPS-treated hippocampal astrocytes and attenuates cell death caused by ROS accumulation, 102 which has been considered as one of the important causes of depression.Additionally, as for the mitochondrial fusion and fission, Suwanjang et al. 103 demonstrated that Spilanthes acmella Murr.
Extract significantly decreases the level of Drp1 in the hippocampus of chronic restraint stress rats.Based on the above information, it would imply that besides mitochondrial biogenesis, some antidepressants may also exert their antidepressant effects by enhancing mitophagy or balancing mitochondrial fusion and fission.

| CON CLUS I ON S AND FUTURE OUTLO O K
This review emphasizes the vital roles of mitochondria in the pathogenesis of depression.It is noteworthy that impaired mitochondrial energy metabolism and damaged quality control systems have been proved to be involved in the development of depression (Figure 2), and some antidepressants exert their effects at least partly by Abbreviations: 5-HT, 5-hydroxytryptamine; AMPK, 5′-AMP activated protein kinase; BNIP3L/NIX, BCL2 interacting protein 3 like; Drp1, Dynaminrelated protein 1; GABAA, gamma aminobutyric acid A; LSD1, lysine specific demethylase 1; MTNR, melatonin receptors; NET, norepinephrine transporter; NMDA, N-methyl-D-aspartate; NRF1, nuclear respiratory factor 1; PGC-1α, peroxisome proliferator-activated receptorγ coactivator 1α; PRKAB1, 5′-AMP-activated protein kinase subunit beta-1; SERT, serotonin transporter; SIRT1, silent information regulator-1; SNRIs, serotoninnoradrenaline reuptake inhibitors; SSRIs, selective serotonin reuptake inhibitors; TFAM, mitochondrial transcription factor A; TSPO, translocator protein 18 kDa.F I G U R E 2 Simplified scheme of mitochondrial disorder as a mechanism underlying depression.Impaired brain energy metabolism and (or) damaged mitochondrial quality control systems may lead to depression.
demonstrated that CUMS severely disrupts mitophagy in hippocampus, while elevated mitophagy can ameliorate depression-like behavior in mice.It is generally accepted that mitophagy pathways include the PTEN-induced putative kinase 1 (PINK1)/Parkin pathway and the receptor-mediated mitophagy pathway.The PINK1/Parkin pathway refers to PINK1 recruits Parkin to the depolarized mitochondria, and Parkin promotes mitophagy via the ubiquitination of outer mitochondrial membrane proteins and the recruitment of Ub-binding autophagic components, which is believed to be the TA B L E 1 The changes of proteins related to mitochondrial quality control systems in studies of depression.
improving mitochondrial function.This review may provide a new insight to study the underlying mechanisms in depression, and be of guiding value to explore new antidepressants specially designed to target mitochondria.Despite these insights, there are still some gaps in our understanding of the mitochondrial mechanisms underlying depression.It is known that multiple mechanisms may contribute to depression, including monoamine neurotransmitter deficiency, hypothalamicpituitary-adrenal (HPA) axis dysregulation, neuroinflammation over-activation, etc., but how does the relationship between the mitochondrial mechanisms and other classical mechanisms of depression?Moreover, many factors have been found to be involved in the processes of mitochondrial energy metabolism and quality control systems, as well as play crucial roles in depression.What are the reasons for the varying expression of mitochondrial-related proteins in different types of depression or depressive animal models?Howto explain the association between mitochondrial dysfunction and the underlying signaling networks?The complex interplay between these pathways complicates the identification of specific targets for novel medication development.Difficult-to-treat depression, that is "treatment-resistant depression", is used for patients with depression symptoms that continue to cause significant burden despite the usual treatment efforts.It has been reported some patients with treatment-resistant depression are diagnosed with mitochondrial encephalomyopathy with lactic acidosis and some novel antidepressants exert a rapid antidepressant effect in these patients in part by alleviating mitochondrial dysfunction.104,105Then, whether are the abnormalities of mitochondria and signaling networks similar in different types of depressive disorders, including treatment-resistant depression?What are the differences among the effects of different antidepressants on mitochondria?Addressing these remaining questions would increase the understanding of mechanisms of depression and action of antidepressant drugs, and then aid the development of novel effective therapies to target specific mitochondrial functions.
The antidepressants related to mitochondria.
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